Mortality and morbidity among patients with end-stage renal disease treated by hemodialysis in the United States are high, despite recent improvements in dialysis techniques. NIDDK plans to conduct a controlled trial to determine the effect of interventions to reduce the high morbidity and mortality. The proponents of this application were selected to develop a protocol and participate in an on-going pilot study to test the feasibility of a full-scale study. The full-scale study is a randomized trial of the effect of two independent interventions, employing a 2x2 factorial design and an intention-to-treat analysis of mortality and morbidity. 1) Prescription of a higher dose of dialysis, defined and monitored by parameters from variable volume, double pool (VVDP) urea kinetic modeling. The goals for KT/VVVDP are 0.9-1.1 and 1.3-1.5. Dialysis time (T) will be prescribed according to urea volume (V) and will be the same in both KT/V groups. 2) Prescription of high-flux dialysis membranes, defined by ultrafiltration coefficient and sieving coefficient for beta2-microglobulin. In addition, the high-flux membranes are required to be biocompatible, as defined by reduction in complement and neutrophil levels, whereas the low-flux membranes are required to be bioincompatible. Clinical centers are required to randomize 60 patients over a period of 1 1/2 years. Patient follow-up will be from 1 to 6 1/2 years. Patients who die or discontinue hemodialysis at the center will be replaced, to maintain an average of 60 concurrent randomized patients during the first 5 1/2 years. Depending on the mortality rate, 112-123 patients at each center may be randomized. The statistical power to detect a 20% reduction in 5-year mortality due to each intervention is greater than 90%. Key personnel, patient population and institutional resources are ideal to perform the study. The principal investigator, as a dialysis unit director for nine years and as vice-chairman for the NIDDK-sponsored MDRD Study, has expertise both in hemodialysis and in clinical trials. The co- principal investigator is a current dialysis unit director and has expertise in assessment of health status and comborbidity in hemodialysis. The study team has been together for five years, is experienced in hemodialysis and has excelled in past NIDDK-sponsored clinical trials. The study will be conducted at three dialysis units with 235 out-patients. Based on chart review, 142 patients are currently eligible for entry into the proposed study, which is adequate for participation in the full-scale study.